The influence of chemical sympathectomy on pain responsivity and alpha 2-adrenergic antinociception in neuropathic animals.

We studied the effect of chemical sympathectomy by 6-hydroxydopamine (6-OHDA) on pain behavior and alpha(2)-adrenergic antinociception in rats with a spinal nerve ligation-induced neuropathy. For assessment of alpha(2)-adrenergic antinociception, the rats were treated systemically with two alpha(2)-adrenoceptor agonists, one of which only poorly (MPV-2426) and the other very well (dexmedetomidine) penetrates the blood-brain barrier. Moreover, the effect of MPV-2426 on spontaneous activity of dorsal root nerve fibers proximal to the nerve injury was determined. Systemic treatment with 6-OHDA produced a marked decrease in immunocytochemical labeling of sympathetic nerve fibers in the skin but it produced no marked change in basal pain sensitivity to mechanical stimulation either in neuropathic or sham-operated animals. Systemic administration of MPV-2426 and dexmedetomidine produced a dose-dependent tactile antiallodynic effect in neuropathic animals. Intraplantar injection of MPV-2426 had an identical antiallodynic effect independent of whether it was injected into the neuropathic or contralateral hindpaw. In a test of mechanical nociception and hyperalgesia, dexmedetomidine markedly attenuated pain responses in all experimental groups, whereas MPV-2426 had a weak but significant pain attenuating effect only in neuropathic animals. In the tail flick test, both alpha(2)-adrenoceptor agonists had a significant antinociceptive effect. The pain attenuating effect of MPV-2426 was enhanced by pretreatment with 6-OHDA, except in a test of tactile allodynia. MPV-2426-induced modulation of spontaneous activity was not a general property of dorsal root fibers proximal to the injury. The results indicate that a chemical destruction of sympathetic postganglionic nerve fibers innervating the skin does not markedly influence cutaneous pain sensitivity nor is it critical for the alpha(2)-adrenoceptor agonist-induced attenuation of pain behavior in neuropathic or non-neuropathic animals. Chemical sympathectomy, independent of neuropathy, enhanced the pain attenuating effect by MPV-2426, probably due to a peripheral action, whereas in non-sympathectomized control and neuropathic animals peripheral mechanisms have only a minor, if any, role in the alpha(2)-adrenoceptor agonist-induced antinociception.

Neuropeptides in experimental and degenerative arthritis.

Classical symptoms of both inflammatory and degenerative arthritides may contribute to neurogenic responses like wheal, flare, edema, and pain. Rheumatoid arthritis (RA) is an autoimmune disease with an immunogenetic background. Neurogenic inflammation has been considered to play an essential role in RA, in part because of the symmetrical involvement (cross-spinal reflexes) and the predominant involvement of the most heavily innervated small joints of the hands and the feet (highly represented in the hominiculus). In contrast, osteoarthritis (OA) is considered to arise as a result of degeneration of the hyaline articular cartilage, which secondarily results in local inflammation and pain. However, it is possible that the age-related and predominant (compared to nociceptive nerves) degeneration of the proprioceptive, kinesthetic and vasoregulatory nerves can represent the primary pathogenic events. This leads to progressive damage of tissue with extremely poor capacity for self-regeneration. Inflammation, be it primary/autoimmune or secondary/degenerative, leads to peripheral sensitization and stimulation, which may further lead to central sensitization, neurogenic amplification of the inflammatory responses and activation of the neuro-endocrine axis. Neuropeptides serve as messengers, which modulate and mediate the actions in these cascades. Accordingly, many neuropeptides have been used successfully as experimental treatments, most recently VIP, which effectively controlled collagen-induced arthritis in mice. Therefore, it can safely be concluded that better treatment/control of disease activity and pain can be achieved by blocking the cascade leading to initiation and/or amplification of inflammatory process combined with effects on central nociceptive and neuroendocrine responses.

Fatigue and health profile in sicca syndrome of Sjögren's and non-Sjögren's syndrome origin.

OBJECTIVE: To assess the health status and fatigue in sicca patients with or without Sjögren's syndrome (SS) and to test whether the immune-inflammatory activity or the extent of the disease predict fatigue in SS. METHODS: The Medical Outcomes Study Short-Form General Health Survey (MOS SF-36) was used in 1 degree SS (n = 90), 2 degrees SS (n = 24), non-SS patients with sicca symptoms (n = 15) and healthy population controls (n = 126). Laboratory values and clinical findings were used to predict fatigue in SS. RESULTS: 74% of the SS and 80% of the non-SS sicca patients felt themselves tired. Vitality score values were 40.2 +/- 20.3 in 1 degree SS, 42.1 +/- 20.6 in 2 degrees SS and 29.0 +/- 15.8 in non-SS. The health profiles were similar in 1 degree and 2 degrees SS, worse (p < 0.001) than in normal controls, but in most aspects better than in non-SS sicca patients. In SS neither hemoglobin, ESR nor CRP predicted fatigue. Surprisingly, high serum IgG (p < 0.05), antinuclear antibodies (ANA) (p < 0.01) and SS-A antibodies (p < 0.05) values correlated positively with vitality. The number of disease manifestations correlated negatively with vitality (p < 0.004). The total number of disease manifestations, and ANA and/or SS-A autoantibodies were the best predictors of fatigue, but explained it only to 17-57%. CONCLUSION: Patients with fatigue and perceived ill health but without fibromyalgia had sicca symptoms and low basal tear and salivary secretion rates, indicating that cortical events can lead to a SS-like sicca syndrome. Even in SS fatigue is only in part explained by clinical disease manifestations and laboratory tests assessing inflammation and autoimmunity. Fatigue in both SS and non-SS sicca syndrome more likely correlates to other features, such as neuroendocrine aspects of the disease.

Modulation of visceral nociceptive responses of rat spinal dorsal horn neurons by sympathectomy.

We determined whether sympathectomy modulates visceral nociception under physiological or inflammatory conditions. Recordings of sacral spinal dorsal horn neurons with sustained responses were performed in pentobarbitone-anesthetized rats. Graded colorectal distension (CRD, 20-100 mmHg) was used as a visceral nociceptive stimulus. Inflammation was induced by intracolonic instillation of turpentine (25%). Sympathectomy was produced by administering 6-hydroxydopamine. Inflammation produced an increase in the CRD-evoked responses. The CRD-evoked responses were attenuated following sympathectomy both under control and inflammatory conditions. These changes in the CRD-evoked responses were associated with corresponding changes in spontaneous discharge rate. The convergent input evoked by noxious pinch of the skin was not changed by any of the experimental conditions. The results indicate that sympathectomy attenuates visceral nociceptive responses and spontaneous activity of sacral spinal cord neurons, without effect on convergent cutaneous inputs, both under physiological and inflammatory conditions.

High-turnover periprosthetic bone remodeling and immature bone formation around loose cemented total hip joints.

Aseptic loosening and periprosthetic osteolysis are the major problems awaiting solution in total hip surgery. The clinical investigation focused on the analysis of periprosthetic bone remodeling to clarify one important key event in the cascade of periprosthetic connective tissue weakening and osteolysis around loose artificial hip joints. Twelve acetabular bone samples adjacent to granulomatous synovial-like membrane of loose hip prosthesis were retrieved at revision surgery and processed for Villanueva bone staining for morphological observation and bone histomorphometric analysis. Eight well-fixed bony samples were used as control. Although osteoclastic surface and eroded surface by osteoclasts were evident in the periprosthetic bone from loose hip joints (p = 0.003 and p = 0.027), increased osteoid/low-mineralized bone matrix (p < 0.001) and osteoid width (p < 0.001) also were significant findings in structural analysis. In addition, not only elevated mineral apposition rate (MAR; p = 0.044) but also increased mineralizing surface (p = 0.044) and bone formation rate (BFR; p = 0.002) in loose periprosthetic bones were shown in dynamic data analysis. These results were confirmed by precise morphological observation by confocal laser scanning microscopy. Active coupling of bone formation and resorption and increased osteocytes with abundant bone canalicular projections were found in combined with the presence of immature bone matrices (osteoid and low-mineralized bone areas) in periprosthetic bones from loose hip joints. These results indicated that active osteoclastic bone resorption and/or defective bone formation are coupled with monocyte/macrophage-mediated foreign body-type granuloma in the synovial-like interface membrane of loose hip joints. Thus, this unique high-turnover periprosthetic bone remodeling with bad bone quality probably is caused by the result of cellular host response combined with inappropriate cyclic mechanical loading. The fragile periprosthetic bone may contribute to hip prosthesis loosening.